Is NBAS p.Arg683His (c.2048G>A) pathogenic?

NBAS p.Arg683His (c.2048G>A) is classified Conflicting classifications of pathogenicity in NBAS (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-19). AlphaMissense: likely benign (0.0899); Ultra-rare (popmax 0.0434%, amr); Associated with Inborn genetic diseases.

What condition is associated with NBAS p.Arg683His (c.2048G>A)?

NBAS p.Arg683His (c.2048G>A) is associated with Inborn genetic diseases (ClinVar).

How common is NBAS p.Arg683His (c.2048G>A) in the general population?

NBAS p.Arg683His (c.2048G>A) is ultra-rare (popmax 0.0434%, amr) (gnomAD).

What do computational predictors say about NBAS p.Arg683His (c.2048G>A)?

AlphaMissense predicts likely benign (score 0.0899) — an in-silico prediction, not a clinical call.

NBAS p.Arg683His

c.2048G>A · rs774711181 · VCV1493220

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0899 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0434%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0899	likely benign
REVEL	0.311	indeterminate
SaProt	LLR -6.98	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 394 kb · p 0.09 · regional, not allelic
Overall
CADD	28.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0434% Admixed American · 26/59,970 alleles

Filtering AF 0.0304% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.026%

Overall 0.00242% 39/1,613,326 alleles · ultra-rare exomes 37/1,461,170 · genomes 2/152,156 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0434%	2,307
Finnishnot grpmax-eligible	0.00156%	64,000
South Asian	0.0011%	91,070
European (non-Finnish)	0.000933%	107,232

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: NBAS
Protein: p.Arg683His
Coding: c.2048G>A
MANE Select: NM_015909
dbSNP: rs774711181
Type: single nucleotide variant
Location: chr2:15467378 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.42
Residue 683: a UniProt-annotated variant site (in ilfs2; uncertain significance); a UniProt-annotated variant site (found in a patient with a multisystem disease involving liver, eye, immune system, connective tissue and bone; uncertain significance); a UniProt-annotated variant site (found in a patient with a multisystem disease involving liver, eye, immune system, connective tissue and bone; uncertain significance; reduced protein expression levels in fibroblasts); the 'interaction with use1' region

Full NBAS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NBAS p.Arg683Cys Uncertain significance ★ ⚠ same residue
NBAS p.Ala1568Val Uncertain significance ★★ ⚠ same condition
NBAS p.Ala1645Val Uncertain significance ★★ ⚠ same condition
NBAS p.Ala1795Val Uncertain significance ★★ ⚠ same condition
NBAS p.Ala1941Gly Uncertain significance ★★ ⚠ same condition
NBAS p.Ala195Thr Uncertain significance ★★ ⚠ same condition
NBAS p.Ala2005Thr Uncertain significance ★★ ⚠ same condition
NBAS p.Ala2341Val Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/nbas-p-arg683his (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown